Malignant hyperthermia (MH) is a life-threatening hypermetabolic syndrome that occurs when genetically predisposed individuals are exposed to certain anesthetic agents. Although of rare occurrence, several members of an individual family may be affected and medical management of these susceptible individuals is problematic and sometimes refused at most medical centers. This is based on lack of understanding of exactly how the disease is inherited, what triggers the syndrome, and absence of a simple, noninvasive diagnostic test. This proposal contains experimental protocols designed to broaden our understanding of the etiology of the disease, and to explore for new, less invasive diagnostic tests that can be applied at most medical centers. Our MH diagnostic center performs about 75 diagnostic tests per year and we also maintain a MH porcine animal model. Based on several studies in MH man and swine, abnormalities are known to occur in skeletal muscle. We recently discovered a defect in Ca2+ release channels in sarcoplasmic reticulum (SR) membranes that regulate changes in Ca2+ concentration for contraction and relaxation of MH pig muscle. Our preliminary studies suggest that this Ca2+ channel may also be abnormal in MH human muscle and our experiments are designed to test such a hypothesis. The primary goal is to isolate from HM and normal human skeletal muscle SR membrane fractions that are uniform for biochemical and pharmacologic properties and then to compare these functions among membranes obtained from different MH diagnostic groups. Other experiments are designed to study the composition of these SR membranes as well as their biophysical properties. Also, breeding experiments in pigs are planned to give us more information on how these defects are genetically determined and how to apply this information to human MH. We have involved collaborators with unique expertise to help explore precise biochemical and biophysical properties of the SR membranes and to investigate substrate cycling in the MH susceptible individuals. Simpler, noninvasive diagnostic tests on blood cells and on skeletal muscle function are designed to explore for less invasive diagnostic tests for MH. The information obtained will provide a basis for understanding the pathogenesis, form a diagnostic base, and give rationale for prevention and/or treatment of malignant hyperthermia during general anesthesia.